Natural inspired piperine-based sulfonamides and carboxylic acids as carbonic anhydrase inhibitors: Design, synthesis and biological evaluation

Eur J Med Chem. 2021 Dec 5:225:113800. doi: 10.1016/j.ejmech.2021.113800.

Diaaeldin M Elimam ¹, Abdullah A Elgazar ², Alessandro Bonardi ³, Mohamed Abdelfadil ⁴, Alessio Nocentini ³, Ramadan A El-Domany ⁵, Hatem A Abdel-Aziz ⁶, Farid A Badria ⁷, Claudiu T Supuran ⁸, Wagdy M Eldehna ⁹

Affiliations

1 Department of Pharmacognosy, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt; School of Chemistry and Biosciences, Faculty of Life Sciences, University of Bradford, Bradford, United Kingdom.
2 Department of Pharmacognosy, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt.
3 Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Polo Scientifico, Via U. Schiff 6, 50019, Sesto Fiorentino, Firenze, Italy.
4 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt.
5 Department of Microbiology and Immunology, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, P.O. Box 33516, Egypt.
6 Department of Applied Organic Chemistry, National Research Center, Dokki, Cairo, 12622, Egypt.
7 Department of Pharmacognosy, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt.
8 Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Polo Scientifico, Via U. Schiff 6, 50019, Sesto Fiorentino, Firenze, Italy. Electronic address: claudiu.supuran@unifi.it.
9 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt. Electronic address: wagdy2000@gmail.com.

PMID: 34482273 DOI: 10.1016/j.ejmech.2021.113800

Abstract

The natural product piperine, the major bioactive alkaloid present in black pepper fruits, has the ability to modulate the functional activity of several biological targets. In this study, we have utilized the natural piperine as a tail moiety to develop new SLC-0111 analogues (6a-d, 8 and 9) as potential Carbonic Anhydrase inhibitors. Thereafter, different functionalities, free carboxylic acid (11a-c), acetyl (13a) and ethyl ester (13b-c), were exploited as bioisosteres of the sulfamoyl functionality. All piperine-based derivatives were assessed for their inhibitory actions against four human (h) CA isoforms: hCA I, II, IX and XII. The best hCA inhibitory activity was observed for the synthesized primary piperine-sulfonamides (6a-d and 8). In particular, both para-regioisomers (6c and 8) emerged as the most potent hCA inhibitors in this study with two-digit nanomolar activity against hCA II (K_Is = 93.4 and 88.6 nM, respectively), hCA IX (K_Is = 38.7 and 68.2 nM, respectively), and hCA XII (K_Is = 57.5 and 45.6 nM, respectively). Moreover, piperine-sulfonamide 6c was examined for its anti-cancer and pro-apoptotic actions towards breast MCF-7 Cancer cell line. Collectively, piperine-based sulfonamides could be considered as a promising scaffold for development of efficient Anticancer candidates with potent CA inhibitory activities.

Keywords

Anticancer; Benzenesulfonamide; Piperic acid; SLC-0111 analogues; hCA IX inhibitors.

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